A decade on from Dolly

By Rebecca Morelle
Science reporter, BBC News

See the animals in the cloning hall of fame In pictures

The unveiling of Dolly 10 years ago marked the beginning of a new era for science.

A humble Finn Dorset sheep had turned on its head the widely held belief that mammalian cloning from adult cells was a scientific impossibility.

Dolly, who was created at the Roslin Institute in Edinburgh, was actually born on 5 July 1996 although her arrival was revealed on 21 February 1997.

But in the decade that has passed since, has the science of "duplication" lived up to researchers' expectations and where might it lead us next in the not-so-distant future?

"I am slightly disappointed by the fact that, technically, cloning is only slightly better than it was originally," explained Professor Ian Wilmut, one of Dolly's creators who is now based at Edinburgh University.

Genetic material

It took 277 attempts to create one sheep back in 1997. Today, on average, it takes about 150 to 200 attempts to create one clone. Better, but not by much.

It turns out that somatic cell nuclear transfer - the process used to create Dolly and her cloned peers - is just not that efficient.

Quick Guide: Cloning

The technique involves removing the nucleus of one cell from a donor animal and transferring it into an unfertilised egg that has had its own genetic material removed. Add an electric jolt and/or chemicals, and, hey presto, the egg begins its transformation into the identikit embryo.

The tricky bit lies in getting the donor cell, say the skin cell, to "forget" that it is a skin cell, and to begin behaving like a stem cell - a cell that can transform into any other cell in the body - so it can go on to make a cloned embryo.

"To be honest, I think we should still be surprised that cloning works at all. Before Dolly, people thought it was impossible," Professor Wilmut tells the BBC News website.

Now, research is under way to understand cell "reprogramming".

Professor Wolf Reik, from the Babraham Institute, Cambridge, said: "We are starting to identify certain enzymes that strip out this existing memory, but it is becoming apparent that there are a number of factors involved.

"To improve cloning efficiency you would put these critical combinations together, in the right mix, and apply it to the cell to persuade it to lose its memory and begin again."

Development quirks

But crack this for one species and you still haven't solved the complexities of cloning - it also turns out that early development in different mammalian species is incredibly varied.

Dr Teruhiko Wakayama, of the Center for Developmental Biology in Riken, Japan, was part of the team that created the first cloned mouse, Cumulin, born in 1997.

He said: "Mouse cloning is much more difficult than creating cow, sheep or pig clones. Only a few laboratories can make cloned mice continuously; other laboratories can make only cloned blastocysts (early-stage embryos), but not full-term offspring."

CLONED MAMMALS Sheep (1996) Mouse(1997) Cattle (1998) Pig (2000) Goat (2000) Gaur (2001) Cat (2001) Rabbit (2001) Mule (2003) Horse (2003) Deer (2003) Rat (2003) African wildcats (2004) Dog (2005)

He says this is because each species has a different and specific nuclear transfer "recipe", or protocol, required for cloning success.

However, while the success rate for cloning remains low, this does not mean the technology has ground to a halt: scientists still see great scientific and commercial potential.

James Robl is one of the creators of cloned calves George and Charlie, which were born in 1998. But the cows were not just clones - they had been genetically engineered too.

Altering an animal's DNA to give it special characteristics is not easy, and in some species, cloning to copy these successful changes many times over offers the only viable way of doing this.

Some scientists are using this to create animals with organs that could be transplanted into humans. But closer to fruition, perhaps, is the work going on to create animals that can produce medical products, a field known as "pharming".

Dr Robl, president of Hematech, based in South Dakota, said: "We [Hematech] do cloning on a very large scale: last year, we transferred 4,000 cloned embryos.

Stem cell guide:
What are stem cells and what might they be used for?

At-a-glance

"And we can do some very, very complicated genetic modifications with these animals. It has allowed us to make substantial progress towards our goal of making a cow that makes human polyclonal antibodies for human therapeutic applications."

Animal cloning is also being given commercial consideration for agriculture. In the US, the Food and Drink Administration recently reported food produced by cloned cattle, pigs and goats was "as safe as the food we eat every day".

Professor Keith Campbell, one of Dolly's creators, now based at Nottingham University, said: "The idea would be to use cloning to introduce beneficial genetic changes into animals or to reproduce superior genetic animals to breed back into the population.

"There would be some benefits to this. For example, if you could make animals that were resistant to certain diseases, then the animal would have a better life, the farmer would be better off, and we wouldn't need to douse the animals with antibiotics."

However, he believes that public acceptance could delay its introduction into the market.

Human futures

While many efforts have been focused on animal research, the prospect of human cloning has attracted the most attention.

Dolly is now on display at the Royal Museum, Edinburgh More details

And much research has been focused on therapeutic cloning, which uses cell nuclear transfer to create an embryonic stem cell rather than a whole organism.

So far, scientists have been unable to produce human embryonic stem cell lines, but the hope is that once created they will help scientists understand and perhaps cure a whole host of human diseases.

Professor Alan Trounson, director of the Institute of Reproduction and Development at Monash University, Australia, says he is cautiously optimistic about therapeutic cloning, but "it is still incredibly inefficient, and to my mind has not really been successful".

Part of the problem, he says, is that the large numbers of eggs needed to carry out the technique are just not readily available.

In terms of reproductive cloning, humans are noticeably absent from the cloning role-call.

But Professor Ian Wilmut says this is no bad thing. "It is a great shame that we haven't been able to come together to set up a global prohibition of human reproductive cloning, so it is judged as a crime against humanity.

"A lot has happened since Dolly," he added.

Dolly died in 2003. Her stuffed remains are on show at Edinburgh's Royal Museum.